The immune system is a complex system of molecular and cellular defenses that recognize potentially harmful exogenously or endogenously derived antigens. When stimulated, the immune system undergoes a series of activities that results in an immune response that is cell-mediated, antibody-mediated (i.e., humoral), or a combination of both.
A large part of the cell-mediated immune response is the activation of T cells through the recognition of and response to antigen presentation. It has long been recognized that antigens derived from polypeptides are presented to T cells through a group of molecules known as major histocompatibility complex (MHC) molecules. In MHC-mediated presentation, the T cell antigen receptor recognizes a peptide in combination with an MHC molecule. In general, antigens presented by MHC class I molecules are recognized by CD8+ T cells, while antigens presented by MHC class II molecules are recognized by CD4+ T cells. See, for instance, the description of MHC molecules and their antigen presentation in U.S. Pat. Nos. 5,679,347; 5,853,737 and 6,238,676.
Recently, it has also been recognized that antigen presentation occurs through a distinct family of antigen presenting molecules, CD1 molecules. In humans, five CD1 genes have been identified: CD1a, CD1b, CD1c, CD1d and CD1e. These proteins are displayed on antigen presenting cells which include Langerhans cells, activated B-cells, dendritic cells in lymph nodes, activated blood monocytes, etc. Although there is a structural resemblance to MHC molecules, CD1 molecules differ from MHC molecules in a variety of ways. For instance, CD1 genes are apparently non-polymorphic, while human MHC genes are highly polymorphic. Additionally, until the instant invention, CD1 molecules were believed capable of presenting only non-peptide antigens, unlike MHC molecules.
Responses to non-peptide antigens have been previously reported. For example, CD4− CD8− and CD8+ T cells expressing αβ T cell receptors (TCRs) recognized M. tuberculosis lipid and lipoglycan antigens presented by CD1b proteins and, as a result, exhibited measurable proliferation and interferon-γ secretion (Porcelli et al. Nature 1992, 360(6404):593-7; Stenger, S., et al., Science 276:1684-1687 (1996)). In another study, two CD8+ TCR αβ+ T cell lines displayed cytotoxicity and strong Th cell type I cytokine response as a result of the recognition of M. tuberculosis antigens when presented by CD1a or CD1c proteins (Rosat et al., Journal of Immunology 162:366-371 (1999)).
Beyond being involved in the response of the immune system to bacterial invasion, CD1-presentation may also play a role in autoimmune disease. CD1 molecules have been shown to be recognized by CD4−CD8− T cells derived from patients with SLE (Porcelli, et al., Nature 341:447-450 (1989)), and even though no foreign antigen was present, leukemia cells expressing CD1 molecules were lysed by the T cells. More recent studies have shown that self lipids like phosphatidylinositols, gangliosides and sulfatides can lead to T cell activation in vitro and in human disease. (Shamshiev et al. Eur J Immunol. 1999, 29(5):1667-75; Gumperz et al. Immunity. 2000 February;12(2):211-21.) In addition, CD1d proteins have been shown to modulate T cell responses to tumors in ways that affect the final outcome of immune mediated diseases (Moodycliffe et al. 2000, Nat. Immunol. 1:521-525; Terabe et al. Nat Immunol. 2000, 1(6):515-20; and Cui et al. Science, 1997, 278(5343):1626-9.)
Due to the involvement of CD1 presentation in stimulating T cell responses, new CD1-presented antigens would be useful in augmenting and/or polarizing immune responses. These antigens would therefore be useful in detecting and treating microbial (e.g., bacterial) infections, autoimmune diseases or other diseases in which T cells play a role.